Hyperlipidemia is a pathological state in mammals, where there is an abnormally high concentration of lipids circulating in the serum. The composition of the lipid pool in the circulation consists mostly of triglyceride (fatty acid esters of glycerol), cholesterol, and fatty acid esters of cholesterol. Such lipophillic molecules are poorly soluble in the aqueous environment of the serum and are, therefore, rarely found as free entities in the circulation. Such molecules are generally found bound to specific proteins in the form of complexes which act as transporting mechanisms. The specific, lipid carrying proteins are known as a class as apoproteins. Various combinations of different and specific lipids and apoproteins form particles (lipoproteins) which serve both to transport lipids and perform specific biological functions. In general, such particles are physically classified by their density, e.g., high density lipoproteins (HDL)--1.063-1.210 g/mL, low density lipoproteins (LDL)--1.019-1.063 g/mL, very low lipoproteins (VLDL)--&lt;1.006 g/mL, etc. In addition, each of these particles contains a specific profile of lipid composition, e.g., HDL contains mostly cholesterol and its esters, whereas LDL's contain more or exclusively triglycerides.
Common pathological sequelae of hyperlipidemia, especially hypercholesterolemia, are atherosclerosis, hypertension, ischemic events, such as, myocardial infarction, cerebral stroke, and organ insufficiency and thrombosis.
A commonly used index of identifying human patients at risk of the pathological sequelae of hyperlipidemia, is the determination of total serum cholesterol. Generally, in adults, total serum cholesterol levels greater than 240 mg/dL are indicative of potential danger of hyperlipidemia, while levels &lt;200 mg/dL are considered normal. As a rough measurement, these criteria are reasonably accurate. However, total cholesterol does not reflect the relative amounts or ratio of cholesterol in the various lipoproteins, e.g., HDL versus LDL. This ratio of the distribution of cholesterol has also been shown to correlate to the potential risk of developing cardiovascular disease due to hyperlipidemia. Thus, the total amount of cholesterol and its distribution are risk factors.
In a large and long epidemiologic study (Framingham Study), it was shown that hyperlipidemia, especially hypercholesterolemia, is a risk factor for atherosclerosis. However, this study also demonstrated that a high ratio of HDL to LDL decreases the chances of developing atherosclerosis. Therefore, in order to treat or prevent hyperlipidemia, this study suggests that it is more efficacious to both lower the total serum cholesterol and to raise the ratio of HDL to LDL than to only lower total cholesterol levels.
Many drugs are available which lower-total serum cholesterol, e.g., the chemical classes known as the statins. These agents have been useful in both treating and preventing hyperlipidemia. However, these agents have little or no effect on the ratio of HDL to LDL.
Agents or life-styles are known to effect the HDL-LDL ratio, e.g., exercise raises HDL, smoking lowers HDL, small amounts of alcohol raise HDL, and hormones may either raise or lower the ratio. Most germane, to the current invention, is the effect which estrogen has on the HDL-LDL ratio.
Premenopausal women, normally, have higher levels of HDL as than their male counterparts. Premenopausal women also have less cardiovascular disease, especially disease related to hyperlipidemia, as compared to males in the same age group. However, postmenopausal women, or women at the menopause, have an increased risk for cardiovascular disease sometimes even surpassing the risk of their male counterparts. At the menopause, women demonstrate a rapid rise in total serum cholesterol and a lowering of HDL. The exact mechanism of this change is not well understood; however, women, who receive Hormone Replacement Therapy, HRT, (estrogens and/or progestins), show a normalization of total serum cholesterol, HDL-LDL ratio, and a lessening in the risk of cardiovascular disease. Estrogen is believed to exert one of its cardiovascular protecting effects by increasing HDL levels.
Although there are many factors controlling the levels of HDL which are known, the entire control mechanism is not totally understood. One factor thought to be important in this process is the effect of hepatic lipase. Hepatic lipase, a liver enzyme, is a major factor in controlling the degradation of HDL particles. This enzyme facilitates the hydrolysis of HDL phospholipids and triglycerides and the subsequent dissolution of the lipoprotein particle. Recently, it has been found that the gene coding for this enzyme, controlled by many factors, is down-regulated by the hormone estrogen. This down-regulation of the lipase gene and subsequent lowering of the production of the enzyme, may, at least in part, explain the rise in HDL and lowering of cardiovascular risk in postmenopausal women on HRT. (For further information see: "Harrison's Principles of Internal Medicine", Eds. Iselbacher, et al., 9th Ed., McGraw-Hill Co., NYC, Chap. 250, pp. 1159-1168 and Chap.99, pp.507-518 and references therein; and Oka, K. et al., "Transcription of the human lipase gene is modulated by multiple negative elements in HepG2 cells.", Gene, 180, p.69-80 (1996) and references therein.)
Today, HRT is used in women to ameliorate the cardiovascular effects of menopause. This therapy, while effective, suffers from poor patient compliance, due to unpleasant side-effects, poor oral absorption, and poor bio-availability of the natural estrogens 17-b-estradiol and estrone.
Compounds of the current invention, i.e., the compounds of formula I(b), have the potential of down regulating the expression of hepatic lipase, thus raising the levels of HDL. This effect of raising HDL indicates usefulness in treating hyperlipidemia, especially hypercholesterolemia, and its subsequent pathological sequelae. In addition, compounds of the current invention are well absorbed by the oral route and possess favorable bio-availability properties.